Candida albicans is an opportunistic pathogen that causes oropharyngeal disease in a large and diverse population of patients, including those with HIV/AIDS, Sjogren's syndrome, diabetes mellitus, and cancer of the head and neck. Azole antifungal agents are the current mainstay of therapy for oropharyngeal candidiasis. However, because of the emergence of azole resistance, it is critical to develop novel strategies to prevent and treat this disease. Our goal is to identify new C. albicans virulence genes and to determine the mechanisms by which they contribute to pathogenicity. This information holds promise to identify new therapeutic targets for antifungal strategies. C. albicans invades oral epithelial cells by inducing its own endocytosis. In the previous project period, we discovered that C. albicans Als3 is an invasin that binds to E-cadherin on the epithelial cell surface and induces the endocytosis of the organism. Recently, we have determined that there are additional epithelial cell surface proteins that mediate endocytosis. These epithelial cell surface proteins include the globular C1q receptor (gC1qR) and the Met receptor tyrosine kinase. Also, the tetraspanin, CD151 likely organizes E-cadherin, gC1qR, and Met into a functional complex. We have also discovered that the C. albicans kinase, Tpk2 governs the capacity of C. albicans to invade and damage oral epithelial cells in vitro, as well as cause oropharyngeal candidiasis in mice. Further, Tpk2 governs the expression of the C. albicans chitinase, Cht2 and hexose transporter, Hgt12, which play key roles in C. albicans interaction with epithelial cells. In this project, we will 1) determine the functional interactions among E-cadherin, gC1qR, Met, and CD151 in epithelial cell invasion and damage by C. albicans;2) determine the mechanisms by which C. albicans Cht2 and Hgt12 govern epithelial cell invasion, damage, and virulence;and 3) use overexpression-rescue and null mutant analysis to identify additional target genes of Tpk2 that mediate epithelial cell invasion and damage. PUBLIC HEALTH RELEVANCE: This research is highly relevant to public health because oropharyngeal candidiasis is a frequent cause of morbidity in patients with HIV/AIDS, Sjogren's syndrome, diabetes mellitus, and head and neck cancers. Although azole antifungals are currently the mainstay of therapy for oropharyngeal candidiasis, the emergence of azole resistance makes it necessary to develop new strategies to prevent and treat this disease. Discovering the C. albicans genes and host cell receptors that govern epithelial cell invasion and damage holds promise to provide new insight into the pathogenesis of oropharyngeal candidiasis. Furthermore, this information may be used to develop new therapeutic strategies against this highly prevalent disease.